Atherothrombosis, which is caused by arteriosclerosis and induces myocardial infarction, cerebral infarction and the like, and deep vein thrombosis, which induces pulmonary embolism, accounts for a majority of causes of death for human beings. Warfarin, which is currently most frequently used as an anticoagulant agent having the efficacy and effect of the “treatment and prevention of thromboembolism such as vein thrombosis, myocardial infarction, pulmonary embolism, cerebral embolism, slowly progressive cerebral thrombosis, and the like”, exhibits excellent antithrombotic activity. On the other hand, warfarin has problems of causing difficult hemostasis during bleeding and thus severe side effects of hemorrhagic complication. Under such circumstances, it has been strongly desired to develop a therapeutic agent and a preventive agent for thrombosis or thromboembolism, which have a novel action mechanism that suppresses the pathological growth of thrombus while having no influence on hemostasis of blood vessels.
It has been known that many blood-coagulating factors (cascade) are involved in hemostasis and thrombus formation. Hence, if the action mechanism of each blood-coagulating factor was elucidated and a specific blood-coagulating factor of interest could be controlled, it would provide a powerful approach for solving the aforementioned problems. In recent years, it has been found that the factor XI (FXI), one of endogenous blood-coagulating factors, is closely involved in the pathological growth of thrombus (see, for example, Non Patent Literatures 1 and 2). That is to say, it has been revealed that accelerating the step of the blood coagulation cascade, in which activated factor XI (FXIa) is generated from FXI, plays an important role in the pathological growth process of thrombus. Moreover, it has also been revealed that FXI is not involved in the hemostatic process during bleeding. In fact, in a study using FXI knock-out mice, an inhibitory activity against the generation of thrombus has been confirmed to be in a venous thrombus model, but it has been proved that hemostatic time is not affected in the same model (see, for example, Non Patent Literature 3). Therefore, inhibition of FXIa activity will be an extremely appealing approach for solving the aforementioned problem.
Protease inhibitors comprising, as active ingredients, phenylalanine derivatives represented by Formula 1 and Formula 2 are disclosed in Patent Literatures 1 and 2, respectively.
wherein X represents —COY wherein Y represents a lower alkyl group optionally substituted with a specific substituent or the like; R1 and R2 each represent a hydrogen atom, with the proviso that R1 and R2 do not simultaneously represent hydrogen atoms, an alkyl group optionally substituted with a specific substituent, a cycloalkyl group, a phenyl group optionally substituted with a specific substituent, or a pyridyl group optionally substituted with a specific substituent, or R1 and R2 represent, together with a nitrogen atom to which they bind, a cyclic piperidyl group optionally substituted with a specific group; and n represents 4 or 10.
wherein A represents H2N— or the like; B represents —CH2-cyclohexane ring- or the like; X represents a hydrogen atom or the like; and Y represents —NR1R2, wherein R1 and R2 each independently represent a hydrogen atom, with the proviso that R1 and R2 do not simultaneously represent hydrogen atoms, a phenyl group optionally substituted with a specific substituent, a pyridyl group optionally substituted with a specific substituent, a C1 to C4 alkyl group optionally substituted with a specific substituent, or a C5 to C7 cycloalkyl group, or R1 and R2 represent, together with a nitrogen atom to which they bind, a piperidino group optionally substituted with a specific group, or a pyrrolidyl group optionally substituted with a specific group.
These patent literatures describe that an antiplasmin agent, which is one of protease inhibitors, is useful as a hemostatic agent, and that an anti-urokinase agent is useful for suppressing bleeding symptoms during application of thrombolytic therapy (see the “Prior Art” and “Technical Problem” sections in both publications).
Furthermore, a protease inhibitor comprising, as an active ingredient, a phenylalanine derivative represented by the following [Formula 3] is disclosed in Patent Literature 3.
wherein A represents H2N— or the like; B represents —CH2-cyclohexane ring- or the like; X represents a hydroxyl group or the like; and Y represents —NR1R2, wherein R1 and R2 each independently represent a hydrogen atom, a phenyl group optionally substituted with a specific group, a pyridyl group optionally substituted with a specific group, an imidazolyl group, a pyrimidyl group, a tetrazolyl group, a thiazolyl group optionally substituted with a specific group, a C1 to C6 alkyl group optionally substituted with a specific substituent, or a C5 to C7 cycloalkyl group optionally substituted with a specific group, or R1 and R2 represent, together with a nitrogen atom to which they bind, a piperazyl group optionally substituted with a specific group, a piperidino group optionally substituted with a specific group, a pyrrolidyl group optionally substituted with a specific group, or a morpholino group, or represent —OR3 wherein R3 represents a hydrogen atom or the like, or a pyridyl group.
This patent literature describes that a kallikrein inhibitor, which is one of protease inhibitors, is useful as a blood pressure regulator or the like (see the “Prior Art” and “Technical Problem” sections).    Patent Literature 1: JP 63-233963 A    Patent Literature 2: JP 63-238051 A    Patent Literature 3: JP 63-239256 A    Non Patent Literature 1: Blood 2010, 115, 2569.    Non Patent Literature 2: Arterioscler Thromb Vasc Biol 2010, 30, 388.    Non Patent Literature 3: J. Thromb. Haemost. 2006, 4, 1982.